Type 2 diabetes drug, metformin, impacts gut bacteria

Patients with type 2 diabetes have what is called insulin resistance, an inability to properly use insulin. The pancreas will make more insulin to keep blood glucose levels normal however, eventually, the pancreas can’t keep up and drugs may need to be taken. The most common drug to treat type 2 diabetes is metformin. A large team of scientists throughout Europe and China published a study in Nature showing that metformin affected gut bacteria in type 2 diabetics.

The researchers analyzed stool samples from 784 individuals with and without type 2 diabetes and looked at the effects that metformin had on gut bacteria. Metformin is usually prescribed in high doses and because it is a chronic disease, patients end up taking the drug often for many years. Based just on stool samples, they were not able to identify which sample was from a diabetic patient or control unless they took metformin. Type 2 diabetics who were on metformin had higher levels of E. coli and lower levels of I. bartletti than the controls or type 2 diabetics not taking metformin.

Studying the bacteria that changed in abundance in the gut suggested to the scientists that butyrate and propionate had elevated production. These two short chain fatty acids are associated with lowering blood glucose levels.

Importantly, this study helps explain some existing studies with conflicting results comparing gut bacteria of people with and without type 2 diabetes. This was most likely due to the fact that there were more individuals taking metformin in one study than another and this was not controlled for.

This study not only informs us on what is happening with gut microbes after taking metformin but also shines a light onto the importance of controlling for all external factors in microbiome studies, including treatments that could have confounding effects.  

Microbiome affects blood glucose levels after eating, can help predict glycemic response to foods

Postprandial (post-meal) glycemic response (PPGR) is the effect that food has on blood glucose levels.   Eating a sugary candy, for example, will raise blood glucose levels, whereas drinking water will not.  PPGR remains an important predictor for metabolic syndrome and type II diabetes, so it has an important role the obesity epidemic.  Unfortunately, PPGR is difficult to predict, and efforts that are based on individual foods themselves have failed.  New research shows that there are many factors, including the microbiome, that are important to predicting blood glucose after a meal.  The research out of Israel and published in the journal Cell presents a new model that can more accurately predict PPGR that is based on personalized factors.

The researchers catalogued 800 peoples’ meals over 7 days while continuously measuring their blood glucose levels.  In addition they monitored their gut microbiota, weight, sleep, and various other lifestyle factors.  After evaluating the data, the scientists realized that identical foods had vastly different PPGRs.  For example, bread could have a 8 fold variation in glycemic response depending on the individual.  In order to explain these differences, the scientists identified several significant associations between the microbiome and the PPGR from specific foods.  For example, on the phyla level high abundances of Proteobacteria and Enterobacteriaceae were associated with poor glycemic controls.  On the species level Eubacterium rectale, which is known to ferment fiber, was correlated with low glycemic response, and Parabacteroides distasonis, which had previously been associated with obesity, was correlated with hight glycemic response.  The scientists then aggregated all of their data, including microbiome data, and created a predictive algorithm for the PPGR from foods for individuals.  This algorithm accurately predicted the glycemic response from foods on a personalized level, and was more informative than general food based predictions.

This study speaks to the power of personalized medicine that is based on the microbiome.  Knowledge of our own microbiome could be used to advise our dietary choices in order to choose foods that will lead to low PPGR, and decrease our risk for metabolic syndrome.  Overall, the scientists determined that of all foods, eating fiber was most beneficial because it lowers glycemic response over the long term.

Associations between the microbiome and blood lipids

Cholesterol molecule

It is well known that we have to be careful with what foods we eat, remembering to stay healthy and eat our fruits and vegetables. Diets high in fat can create serious health issues such as obesity, high cholesterol, and possibly Type 2 diabetes. Also on that list of related health problems is cardiovascular disease, which is characterized by blood clots, due to fat and plaque build-up in blood vessels, and can lead to a heart attack or stroke. Previous research has implied a connection between the microbiome and cardiovascular disease, due to the microbiome’s effect on production of a molecule called trimethylamine N-oxide (TMAO). As of yet, no research has been done to track the association between the microbiome and lipid (fat) build-up, so this is precisely what researchers published in Circulation Research set out to do.

The scientists located in The Netherlands, Poland, and Massachusetts, collected blood cholesterol measurements from 1500 LifeLines-DEEP subjects. LifeLines-DEEP is a collection of subjects used for assessing various health issues. Ethnic outliers and genetically related participants were removed from the study. Fecal samples were collected from 1180 participants, and sequenced. By the end of the data collection, 99 participants were excluded for reasons such as antibiotic use, or use of potentially microbiome-altering medications. In total there was a final number of 893 participants (380 men and 513 women) for which cholesterol samples, microbiome samples, and genotypic information was obtained. The participants included a wide range of age, BMI, and blood lipid levels.

The researchers found that gut microbiome species richness was significantly higher in women, and increased with age. Microbial richness was positively correlated with high density lipoproteins (HDL, the 'good cholesterol'), not correlated with low density lipoproteins (LDL, the bad cholesterol), and negatively correlated with body mass index (BMI). For example, the study confirmed that lower abundances of kingdom Archaea, families Christensenellaceae and Rikenellaceae, class Mollicutes, and genus Dehalobacterium are associated with high BMI. It was estimated that the microbiome could explain 4.57% to 65 of variation in BMI, triglyceride and HDL. No link was found between the gut microbiome and genetic predisposition to obesity of high blood lipid levels.

One hypothesis raised by the researchers is that bacteria potentially try to correct lipid imbalances, thereby helping to prevent cardiovascular disease. The strong associated between the gut microbiome and BMI and blood lipid levels – regardless of age, sex, and genetics – suggests that the microbiome does indeed play a role, if indirectly, in cardiovascular disease and other fat-related issues. 34 gut bacteria were found to be associated with BMI and blood lipids. There is a real potential for the utilization of this information in health therapies, such as blood clot and stroke prevention.

Interactions of microbiome, diet, and genetics modulate predispostion to diabetes and metabolic syndrome

The human population is undergoing epidemics of metabolic syndromes, type 2 diabetes, and cardiovascular disease and the reasons for these increases in prevalence are not entirely known.  Scientists understand that this rise may be a combination of genetic risk factors as well as environmental risk factors. Scientists from Harvard, Washington University in St. Louis, and the Helmholtz Center in Germany published a paper in Cell Metabolism investigating three strains of mice and analyzing interactions between host genetics, diet, and the gut microbiota.

They used two strains of mice from the Jackson Laboratory (B6J and 129J) and one strain from Taconic Farms (129T). They Taconic strain is very similar to the 129J strain from Jax however it is given a probiotic, resulting in a difference in its gut microbiome. They also inbred the three strains for several generations to create environmentally normalized mouse groups.

They found that the Taconic 129T mice were similar to the 129J mice in their development of diet induced obesity after a high-fat diet but they only developed mild glucose intolerance in comparison to the Jax mouse strain. After inbreeding these mice for three generations in the same environment, these differences were lost. After analysis including 16s sequencing, the original differences in phenotypes and the changes following inbreeding normalization were a result of microbiome differences and microbiome differences were largely dependent on diet, host genetics, and environmental history.  They also found strong strain-dependent and strain-independent relationships between specific phenotypes and bacterial communities that indicated strong interactions between the microbiome, diet, ancestry and genetics.

This study shows that metabolic syndrome and related conditions is the result of complex interactions between genetic and environmental factors, including the gut microbial community. These interactions between diet, genetics, and the microbiome present a significant challenge in the analysis of human disease. 

Helminths may increase sensitivity to insulin

Different helminth eggs

Countries that are becoming more exposed to Westernization have experienced many positive health impacts, such as decreases in infectious disease rates.  At the same time, however, there have been some negative consequences, such as increases in type 2 diabetes (T2DM) patients in these developing countries.  T2DM is linked to disruptions in energy balance and increases in systemic inflammation.  Interestingly, helminth infections – i.e., the parasitic worms that can reside in the intestines – have been previously shown to enhance glucose tolerance in animal models as well as induce anti-inflammatory immune responses.  Researchers sought to explore this relationship in humans, hypothesizing that insulin resistance is lower in subjects with soil-transmitted helminth infection. 

A homeostatic model assessment for insulin resistance (HOMAIR) test was used to examine insulin resistance in 646 adult study participants on Flores Island in Indonesia.  Soil-transmitted helminth (STH) infection is common on this island.  The HOMAIR model measures insulin in blood samples in a well-validated insulin-resistance assay.  Stool samples were also collected from the subjects, and microscopy and PCR were used to detect various helminth species. 

Of the 646 participants, 424 were STH-infected while 222 were not.  In the STH-infected cohort, participants were further categorized by how many different species were found.  Body mass index and waist to hip ratio were significantly lower in the STH-infected group, suggesting STH-infection may be beneficial toward glucose metabolism.  Furthermore, there was an association between the number of distinct STH species present and HOMAIR.  For every additional species found in a subject, there was an incremental decrease in homeostatic insulin resistance. 

These experiments display an interesting causal relationship between STH species and insulin resistance, however there were certainly limitations.  No association was found between subjects in systemic inflammation in infected versus non-infected groups, failing to elucidate modulations of inflammatory pathways that could be correlated with the observed trends.  Additionally, the changes in insulin resistance may be related to a change in body-mass index rather than helminth infection.  Specifically, participants located in more rural areas may have more active, healthier lifestyles, and would be subsequently leaner and thus more sensitive to insulin.  On top of this, patients with helminths tend to exhibit lower weight in general as these parasites significantly affect metabolism. 

Despite these limitations, this study points to an interesting relationship that is deserving of more examination.  This epidemiology research will impact global health policy and can offer good perspective as more nations around the world are on the path toward development.  

Episode 5 of The Microbiome Podcast: Diet and its impact on our microbiota and health with Drs. Erica and Justin Sonnenburg

As we read on yesterday's blog post, dietary fibers alter the microbiome. On this week's episode of The Microbiome Podcast we talked in depth with Drs. Erica and Justin Sonnenburg from Stanford University about dietary fibers and their impact on our microbiota and our health.  Erica and Justin wrote a book that was published today called The Good Gut: Taking Control of Your Weight, Your Mood, and Your Long-term Health. You can buy it here on Amazon and it's a highly recommended read for anyone interested in the microbiome. 

Check out the newest episode on iTunes, Stitcher, or listen on our website. 

We will continue answering your questions on the podcast so please call 518-945-8583 with any questions for us or for next week's guest, Dr. Elaine Hsiao.

See below for more detailed show notes from today's episode: 

(1:17) Dr. Rob Knight received a Creative Promise in Biomedical Science Prize from the Vilcek Foundation. Read more.
(3:09) Rob Knight also published a book called Follow Your Gut: The Enormous Impact of Tiny Microbes. Click here to buy it on Amazon. 
(3:33) uBiome recently began a pregnancy microbiome study to better understand how the bacteria in our bodies change during and after pregnancy. Find out more on the uBiome website. 
(4:56) Microbiome Therapeutics performed a clinical study with an investigational drug in type 2 diabetics taking metformin and found that the drug resulted in more tolerability for patients and fewer side effects than metformin without the drug. Read more.  

In the (9:40) conversation with Erica and Justin Sonnenburg (read more about their research), we talked about several topics pertaining to diet and dietary fiber and its impact on our microbiota and health. We also discussed: 

(11:49) Why they decided to write the book.
(16:05) Their personal experiences having children and the importance of nurturing their health and its impact on their lives.
(17:55) Dietary fibers and differences among various types of fibers in our diets.
(26:15) How fast does diet change the microbiota?
(32:05) Bacteroides thetaiotaomicron and why it is Erica and Justin's favorite microbe and a study Justin published in 2005 while he was in Jeff Gordon's lab. Read the paper here.  
(37:35) How microbiome therapies are going to look in the future. 
(41:00) How eating better can make an impact now on our overall health. Read the seminal obesity and microbiome paper Erica mentions from the Gordon laboratory. 

We also answered two other (44:00) listener questions about phage therapy and organic vs. non-organic baby and adult foods. 

Next week we will be talking with Dr. Elaine Hsiao from Cal Tech so please call 518-945-8583 with your questions about autism and the microbiome as well as the microbiome's ability to regulate serotonin levels.